Metabolism of acetyl derivatives of polyamines in cultured polyamine-deficient rat hepatoma cells.
The acetyl derivatives of polyamines, N1-acetylspermine (N1-AcSPM) and N1-acetylspermidine (N1-AcSPD), are in vitro better substrates of tissue polyamine oxidase than the corresponding non-acetylated polyamines. Rat hepatoma tissue culture (HTC) cells, depleted of their putrescine (PUT) and spermidine (SPD) content by the use of DL-alpha-difluoromethylornithine (DFMeOrn), an irreversible inhibitor of L-ornithine decarboxylase, were used to study in situ the catabolism of these acetyl derivatives of polyamines. Normal intracellular spermidine content was restored by the addition of N1-acetylspermidine to polyamine-deficient cells. Addition of spermine (SPM) did not restore the spermidine content, although this polyamine elevated the spermine content of the cells. N1-Acetylspermidine reestablished normal spermidine levels of the cells and elevated the cellular putrescine content more efficiently and more rapidly than spermidine. Monoacetylputrescine and N1, N12-diacetylspermine (di-AcSPM) were ineffective in restoring putrescine and spermidine contents. These findings support the concept that N1-acetylspermine and N1-acetylspermidine are natural substrates of tissue polyamine oxidase and suggest poor membrane permeability of monoacetylputrescine (AcPUT) and N1, N12-diacetylspermine. Furthermore, they indicate that acetylation of polyamines by the cytosolic acetyl CoA: polyamine N1-acetyltransferase is the rate-limiting step of polyamine catabolism in rat hepatoma cells. Growth inhibition by DL-alpha-difluoromethylornithine was reversed by N1-acetylspermine and N1-acetylspermidine but not by monoacetylputrescine and N1, N12-diacetylspermine. These results suggest again that the antiproliferative effect of DL-alpha-dilfuoromethylornithine is related to inhibition of polyamine biosynthesis.
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D000518:Eflornithine; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D009952:Ornithine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D000097667:Polyamine Oxidase
D000123:Acetyltransferases; D000518:Eflornithine; D009952:Ornithine; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000097667:Polyamine Oxidase; C030992:polyamine N-acetyltransferase